The cells of the sensory epithelium, and not the stria vascularis, are the main cochlear cells related to the genetic pathogenesis of age-related hearing loss

Abstract

Age-related hearing loss (ARHL) is a major health concern among the elderly population. It is hoped that increasing our understanding of its underlying pathophysiological processes will lead to the development of novel therapies. Recent genome-wide association studies (GWASs) discovered a few dozen genetic variants in association with elevated risk for ARHL. Integrated analysis of GWAS results and transcriptomics data is a powerful approach for elucidating specific cell types that are involved in disease pathogenesis. Intriguingly, recent studies that applied such bioinformatics approaches to ARHL resulted in disagreeing findings as for the key cell types that are most strongly linked to the genetic pathogenesis of ARHL. These conflicting studies pointed either to cochlear sensory epithelial or to stria vascularis cells as the cell types most prominently involved in the genetic basis of ARHL. Seeking to resolve this discrepancy, we integrated the analysis of four ARHL GWAS datasets with four independent inner-ear single-cell RNA-sequencing datasets. Our analysis clearly points to the cochlear sensory epithelial cells as the key cells for the genetic predisposition to ARHL. We also explain the limitation of the bioinformatics analysis performed by previous studies that led to missing the enrichment for ARHL GWAS signal in sensory epithelial cells. Collectively, we show that cochlear epithelial cells, not stria vascularis cells, are the main inner-ear cells related to the genetic pathogenesis of ARHL.

Keywords: ARHL; GWAS; age-related hearing loss; cochlea; genetics of age-related hearing loss; single-cell RNA-seq.

Figure 1

Enrichment of different cochlear cell types for ARHL genetic risk signal Enrichment for ARHL signals obtained using the GWASs from Wells et al. and the MAGMA tool. Dashed bar represents the 5% Bonferroni correction threshold. B, B cell; BC, basal cell; CC, chondrocyte; OB, osteoblast; CEC, capillary endothelial cell; DC/PC, Deiters cell and pillar cell; EC, epithelial cell; FB, fibroblast; FC1, fibrocyte 1; FC2, fibrocyte 2; FC3, fibrocyte 3; FC4, fibrocyte 4; HC, hair cell; HeC, Hensen’s cell; IC, intermediate cell; IHC, inner hair cell; IPhC/IBC, inner phalangeal cell and inner border cell; ISC, inner sulcus cell; M/MP, macrophage; MC, marginal cell; Neu, granulocyte/neutrophil; Nudt4+, Nudt4+ pillar cell; OHC, outer hair cell; OSC, outer sulcus cell; PVM_M, perivascular resident macrophage-like melanocyte; RBC, red blood cells; RMC, cells in Reissner’s membrane; SC, Schwann cell; SGC, satellite glial cell; SGN, spiral ganglion neuron; SL, spiral ligament; SMC, smooth muscle cell; SpC/RC, spindle cell/root cell; SV, stria vascularis; T, T cell; TBC, tympanic border cell.

Figure 2

Effect of the dataset’s cellular composition on the results of GWAS signal enrichment tests Enrichment for ARHL obtained when either all the cell types in the Xu. et al. dataset (P28) or only Deiters’ cells, OHCs, and IHCs (inset) were considered in the analysis. Confining the analysis to only the three epithelial cell types significantly attenuates the enrichment of these cells for ARHL signal. Dashed bar represents the 5% Bonferroni correction threshold.